The overall goal of this program is to develop concise, general strategies and methods for the stereoselective synthesis of structurally complex alkaloids. The methods section of the research plan is divided into three broad areas. The first part describes studies directed toward the synthesis of the important anticancer agents vinblastine and vincristine, and their analogs. During the last funding period we developed an efficient, practical synthesis of Aspidosperma alkaloids ("lower" part of Vinca), based on an enantioselective Diels-Alder (DA) reaction that was specifically developed for this application. Our next objective in this project is to complete a practical chemical synthesis of the Vinca alkaloids. In this context, we will develop new concise, asymmetric syntheses of vindoline, the first asymmetric synthesis of catharanthine, the "upper" (velbenamine) part, and develop new methods for coupling the two parts to produce bioactive Vinca alkaloids. Structurally diverse analogs of the Vinca alkaloids will also be prepared. The second part describes the application of the newly developed chemistry to a diverse range of bioactive natural products that are derived biogenetically from geissoschizine, including akagerine, pleiocarpamine, and strictamine. The third part describes concise, general routes to Amaryllidaceae alkaloids and hapalindoles. Both families have members that exhibit significant anticancer activity. The proposed synthetic routes make efficient use of the asymmetric DA chemistry that was developed in our labs during the last grant period. Throughout the research plan section, we provide extensive preliminary results to support the proposed new chemistry. Overall, these investigations are expected to result not only in efficient syntheses of a wide range of indole alkaloids, but also in the development of useful new methodologies, particularly palladium-catalyzed processes and asymmetric Diels-Alder reactions. The methods developed through this work should prove useful to other synthetic endeavors. The work is expected to lead to the synthesis of many biologically active natural products (especially anticancer agents) and their analogs. These synthetic compounds, including advanced intermediates, will be submitted for biological testing. [unreadable] [unreadable]